Bicyclic aminoketones and method for the production thereof



United States Patent ,0 "ice This invention relates to bicyclic aminoketones and a method of preparing bicyclic aminoketones represented by the following general formula:

R1 l CHz.N\ X R2 \l/ I wherein R and R represent alkyl, cycloalkyl, aryl, aralkyl or together with N form an heterocyclic ring, which possibly contains another heteratom, e.g., the pyrrolidine ring, the piperidine ring, the morpholine ring or the piperazine ring which may contain substituents selected from alkyl esters of low molecular weight, and X represents the -CH group or the -CH .CH group.

It is old in the art to react cycloaliphatic ketones with formaldehyde and secondary amines to give aminoketones which include compounds of useful pharmacological activity (cf. Swiss Patent No. 347,829). It has now been found that compounds having useful pharmacological properties may be prepared by employing bicyclo-[2.2.1] heptanone-(2) and bicyclo-[2.2.2]-octanone as starting materials and by reacting the said with formaldehyde and secondary amines.

The novel aminoketones of this invention are prepared by refluxing bicyclo-[2.2.1]-heptanone-(2) or bicyclo- [2.2.21-octanone with. secondary amines or salts thereof and formaldehyde, advantageously in aqueous solution and in the presence of an acid. Unreacted starting ketone may be recovered from the reaction mixture by dissolving the same in an organic solvent or by steam distillation. The resulting aminoketones may be isolated directly from the reaction mixtures as hydrochlorides or after making the reaction mixtures basic as free aminoketones.

aminoketones are sparingly soluble, if at all but their salts, e.g-., the hydrochloride and the methobromide are readily soluble in water, i

The novel aminoketones of the invention have relatively low toxicity (e.g. DL s.c. of AlbinoSWiss-Web- The novel aminoketones of this invention are stable compounds and can be subjected to high vacuum distillation without decomposing. In water the free 3,153,039 Patented Oct. 13, 1964 ster mice is about 800 mg./kg., for 3 -dim-ethylaminoethyl-and 3-piperidino methyl bicyclo [2.2.11) and in animal tests the same show an analgetic activity corresponding to that of acetyl-salicylic acid.

It is to be understood that the obtained aminoketones may be used as intermediates in the preparation of other compounds and as admixtures in other suitable pharmaoeuticals.

Bicyclo [2.2.1] heptanone derivatives are known to have the endo-exo-isomerism form shown below:

, ext:

endo

-in the general formula is in the exo-position because, e.g., in the case of 3 -dimethylaminomethyl-bicyclo [2.2.11-heptanone-(2) the removal of the carbonyl-group according to the method of Huang-Minlon yielded exo-3- dimethylaminoethyl bicyclo[2.2.1]-heptane the configuration of which has been proved.

EXAMPLE 1 g. of bicycle-[2.2.1]-heptanone-(2) (1 mole) was heated under reflux for 20 hours with 123.5 g. of morpholine-hydrochloride (1 mole) and ml. of 40% formaldehyde solution (1.6 moles) to which had been added 1 ml. of concentrated hydrochloric acid. After cooling, unreacted bicyclo [2.2.11-heptanone-(2) was removed by extraction with ether (or directly with steam distillation), the aqueous solution was made alkaline with solid potassium carbonate and again extracted with ether. The ether solution was dried and the ether removed by distillation. The residue was distilled under high vacuum and 3-morpholine-methyl-bicyclo-[2.2.1]-heptanone (2') was collected at l02l06/ 0.04 torr. The yield was 72% as calculated or reacted bicyclo-[2.2.1]-heptanone- (2). The aqueous solution as such may also be evaporated in vacuo and the obtained hydrochloride can be purified by recrystallization from n-propanol. The recrystallized salt melted at 1940-1945 C.

Of some of the new aminoketones of this invention which can be derived from bicyclo [2.2.1] heptanone- (2), the physical data of the free aminoketones as well as the melting points and halogen analysis values of their hydrochlorides and methobromides are given in the fol lowing tables. The procedure described in Example 1 was used for preparing the compounds with the exception of the dimethylaminomethyl compound which was prepared according to Example 2.

Table 1 R Yield as Boiling at M1) calculated N 1 Formula Mol..w. O./Torr. 11, d4 obtained M calc. fromreacted ketone CH3 -N cwrtnNo 167.24 58-6110. 02 1. 4820 0. 9939 47.97 47.94 4s CHa C2115 I N CnHnNO 195. 30 8588I0.1 1.4770 0.9648 57.20 57.17 57 C2Hb Ca 1 I a-N G14Hz5NO 223.35 97-100/02 1.4698 0.9364 66. 42 66. 40 '23 ml. of 33% 'dimethylamino (1 mole), 120 m1. of

Table I-Continued 1 Yield as N Boiling at MS calculated N Formula M01. w. OJ'Iorr. nS'-[[ d obtained MS calc. from reacted N ketone OH; -N CmHzaNO 235. 36 128132/0. 9 1. 5025 1. 0046 69. 07 68. 82

-N OwHmNO 243. 34 132136/0. 03 1. 5338 1. 0490 72. 08 72. 04 62 N C1zH10N O 193. 28 102-104/0. 08 1. 5015 1. 0317 55. 24 54. 97

N C13H21N O 207. 31 102-106/0. 04 1. 5042 1. 0229 60. 03 59. 59

N O CnHmNOz 209. 28 122124/0. 15 1. 5055 1. 0938 56. 79 56. 61 72 N NCH3 C13H22N20 222. 32 118-122/0. 15 1. 5069 1.0364 63. 82 63.52 60 Melting at 38.0-38.5.

Table II R Hydro- Chrystallized from a Percent Percent Methbromide Chrystallized from Percent Percent I chloride solution of- 01 03.10. 01 melting at C. a solution of Br cale. N melting at obtained obtained N 194. 5-195. 0 Ether/ethanol 17. 40 17.40 249. 0-249. 5 Ethanol 30. 48 30.31

C2 5 N 143. 0-1440 Acetone 15.29 15.51 Hygroscopic.

-N 150. 5-151. 5 Ether/isopropanol- 13. 64 13. 57

CH3 N 137. 5139. 0 Ether/acetone 13. 04 13.69 194. 0195. 5 Isopropanoll- 24.19 24. 46

\ dl-lsoprophy- Q ether.

CH3 -N 177. 5-178. 5 Ether/ethanol 12. 67 13. 20 180. 5109. 5 Ethylacetatel- 23. 62 23. 51

\ ethanol.

-N 191. 5-192. 0 d0 I 15. 43 15. 48 213. O213. 5 n-Propanol 27. 72 28.02

I 201.5402 d0 14.54 14.51 250.5-2560 do 26. 43 26. 66

-N 0 7 1940-1945 do 14.42 .14. 63 225. 5226.0 ,do 26.26 26. 24

v N CH3 202. 0-202. 5 Acetone/ethanol 24. 01 23. 28 259. 5-260. 5 Isopropanoll- 25.19 25. 60

g methanol.

1 Dihydroehloride. V

EXAMPLE 2 trated hydrochloric acid were heated under reflux for 20 hours. The mixture was worked up as in Example 1 to give dimethylaminomethyl-bicyclo-[2.2.1]-heptanone- (2) boiling at 58 61/0.02 ton. Yield: 48%. as calcusiormalin solution (1.6 mole) and m1. of concen- 75 lated on the reacted bicycle-[2.2.IJ-he tanOne-(Z).

g. of bicycle-[2.2.1]}heptanone-(2). 1 mole),

Paraformaldehyde may also be employed in place of' formaldehyde.

The preparation of salts is efiected in known manner.

The reactions with bicyclo-[2.2.2]-octanone follow the procedures described in Example 1 and Example 2. E.g., 3 piperidino bicyclo [2.2.2] octanone boils at 115- 120/ 0.03 torn, 11 1.5050, D 1.0159, M calc. 64.20), its methoiodid (from ethanol/ ether (2: 1) melts at 206.5- 208, formula C H NOJ (363.28), calc. C 49.59, H 7.21, and N 3.85, obtained C 49.35, H 7.36, N 3.97.

I claim:

1. A member of the group consisting of (1) a compound having the formula methylene and ethylene; R and R designate a tanone- (2) References Cited in the file of this patent UNITED STATES PATENTS Schlichting et a1. Nov. 25, 1958 Robertson et a1 J an. 29, 1957 i 

1. A MEMBER OF THE GROUP CONSISTING OF (1) A COMPOUND HAVING THE FORMAUL 